After fertilization, remodeling of the oocyte and sperm genomes is essential to convert these highly differentiated and transcriptionally quiescent cells into early cleavage-stage blastomeres that are transcriptionally active and totipotent. This developmental transition is accompanied by cell cycle adaptation, such as lengthening or shortening of the gap phases G1 and G2. However, regulation of these cell cycle changes is poorly understood, especially in mammals. Checkpoint kinase 1 (CHK1) is a protein kinase that regulates cell cycle progression in somatic cells. Here, we show that CHK1 regulates cell cycle progression in early mouse embryos by restraining CDK1 kinase activity due to CDC25A phosphatase degradation. CHK1 kinase also ensures the long G2 phase needed for genome activation and reprogramming gene expression in two-cell stage mouse embryos. Finally, Chk1 depletion leads to DNA damage and chromosome segregation errors that result in aneuploidy and infertility.

• Keywords
• CDC25A phosphatase, CDK1 kinase, CHK1 kinase, cell cycle regulation, early mouse embryos,
• Publication type
• Journal Article MeSH

After fertilization, remodeling of the oocyte and sperm genome is essential for the successful initiation of mitotic activity in the fertilized oocyte and subsequent proliferative activity of the early embryo. Despite the fact that the molecular mechanisms of cell cycle control in early mammalian embryos are in principle comparable to those in somatic cells, there are differences resulting from the specific nature of the gene totipotency of the blastomeres of early cleavage embryos. In this review, we focus on the Chk1 kinase as a key transduction factor in monitoring the integrity of DNA molecules during early embryogenesis.

• Keywords
• Chk1 kinase, DNA damage, cell cycle checkpoint, cleaving embryo,
• MeSH
• Checkpoint Kinase 1 * metabolism   MeSH
• Embryo, Mammalian enzymology   MeSH
• Embryonic Development * genetics   MeSH
• DNA Damage * MeSH
• Animals MeSH
• Check Tag
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Checkpoint Kinase 1 * MeSH

The preimplantation period of embryogenesis is crucial during mammalian ontogenesis. During this period, the mitotic cycles are initiated, the embryonic genome is activated, and the primary differentiation of embryonic cells occurs. All cellular abnormalities occurring in this period are the primary cause of fetal developmental disorders. DNA damage is a serious cause of developmental failure. In the context of DNA damage response on the cellular level, we analyzed the course of embryogenesis and phenotypic changes during the cleavage of a preimplantation embryo. Our results document that DNA damage induced before the resumption of DNA synthesis in a zygote can significantly affect the preimplantation development of the embryo. This developmental ability is related to the level of the DNA damage. We showed that one-cell embryos can correct the first cleavage cycle despite low DNA damage and incomplete replication. It seems that the phenomenon creates a predisposition to a segregation disorder of condensed chromatin that results in the formation of micronuclei in the developmental stages following the first cleavage. We conclude that zygote tolerates a certain degree of DNA damage and considers its priority to complete the first cleavage stage and continue embryogenesis as far as possible.

• Keywords
• DNA damage, micronucleus, mouse embryogenesis, neocarzinostatin, γH2A.X,
• MeSH
• Blastocyst * MeSH
• DNA MeSH
• Embryo, Mammalian * MeSH
• Embryonic Development genetics   MeSH
• Mice MeSH
• DNA Damage MeSH
• Mammals genetics   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• DNA MeSH

Tens of thousands of rapidly evolving long non-coding RNA (lncRNA) genes have been identified, but functions were assigned to relatively few of them. The lncRNA contribution to the mouse oocyte physiology remains unknown. We report the evolutionary history and functional analysis of Sirena1, the most expressed lncRNA and the 10th most abundant poly(A) transcript in mouse oocytes. Sirena1 appeared in the common ancestor of mouse and rat and became engaged in two different post-transcriptional regulations. First, antisense oriented Elob pseudogene insertion into Sirena1 exon 1 is a source of small RNAs targeting Elob mRNA via RNA interference. Second, Sirena1 evolved functional cytoplasmic polyadenylation elements, an unexpected feature borrowed from translation control of specific maternal mRNAs. Sirena1 knock-out does not affect fertility, but causes minor dysregulation of the maternal transcriptome. This includes increased levels of Elob and mitochondrial mRNAs. Mitochondria in Sirena1-/- oocytes disperse from the perinuclear compartment, but do not change in number or ultrastructure. Taken together, Sirena1 contributes to RNA interference and mitochondrial aggregation in mouse oocytes. Sirena1 exemplifies how lncRNAs stochastically engage or even repurpose molecular mechanisms during evolution. Simultaneously, Sirena1 expression levels and unique functional features contrast with the lack of functional importance assessed under laboratory conditions.

• MeSH
• Gene Knockout Techniques MeSH
• Rats MeSH
• RNA, Messenger genetics   MeSH
• Mitochondria genetics   ultrastructure   MeSH
• Mice MeSH
• Oocytes growth & development   metabolism   ultrastructure   MeSH
• Polyadenylation genetics   MeSH
• RNA, Long Noncoding genetics   MeSH
• RNA, Mitochondrial genetics   MeSH
• Transcriptome genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• RNA, Messenger MeSH
• mitochondrial messenger RNA MeSH Browser
• RNA, Long Noncoding MeSH
• RNA, Mitochondrial MeSH

Homologous chromosome segregation during meiosis I (MI) in mammalian oocytes is carried out by the acentrosomal MI spindles. Whereas studies in human oocytes identified Ran GTPase as a crucial regulator of the MI spindle function, experiments in mouse oocytes questioned the generality of this notion. Here, we use live-cell imaging with fluorescent probes and Förster resonance energy transfer (FRET) biosensors to monitor the changes in Ran and importin β signaling induced by perturbations of Ran in mouse oocytes while examining the MI spindle dynamics. We show that unlike RanT24N employed in previous studies, a RanT24N, T42A double mutant inhibits RanGEF without perturbing cargo binding to importin β and disrupts MI spindle function in chromosome segregation. Roles of Ran and importin β in the coalescence of microtubule organizing centers (MTOCs) and MI spindle assembly are further supported by the use of the chemical inhibitor importazole, whose effects are partially rescued by the GTP hydrolysis-resistant RanQ69L mutant. These results indicate that RanGTP is essential for MI spindle assembly and function both in humans and mice.

• Keywords
• RanGTP, importazole, importin β, meiosis I, oocyte,
• MeSH
• Spindle Apparatus physiology   MeSH
• beta Karyopherins genetics   metabolism   MeSH
• Nuclear Proteins genetics   metabolism   MeSH
• Meiosis physiology   MeSH
• Microtubules metabolism   MeSH
• Mutation MeSH
• Mice MeSH
• Oocytes cytology   metabolism   MeSH
• Cell Cycle Proteins genetics   metabolism   MeSH
• ran GTP-Binding Protein genetics   metabolism   MeSH
• Chromosome Segregation MeSH
• Guanine Nucleotide Exchange Factors genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH
• Names of Substances
• beta Karyopherins MeSH
• Nuclear Proteins MeSH
• Cell Cycle Proteins MeSH
• ran GTP-Binding Protein MeSH
• Rcc1 protein, mouse MeSH Browser
• Guanine Nucleotide Exchange Factors MeSH

• Keywords
• DNA damage response, checkpoint, meiosis, oocyte,
• MeSH
• M Phase Cell Cycle Checkpoints genetics   MeSH
• Humans MeSH
• Meiosis genetics   MeSH
• Oocytes growth & development   metabolism   MeSH
• DNA Repair genetics   MeSH
• DNA Damage genetics   MeSH
• Mammals MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Editorial MeSH